This invention relates to hormone replacement therapy.
Progesterone is a steroid hormone that is produced by the ovaries during a woman's child-bearing years. Progesterone is also made, although in smaller amounts, by the adrenal glands in both sexes and by the testes in males. An astonishing variety of physiological functions are mediated by progesterone (See e.g., Lee, 1993, Natural Progesterone, BLL Publishing, Sebastopol, Calif.). For example, progesterone, which surges following ovulation, maintains the secretory endometrium and thus, helps to ensure the survival of the embryo and fetus. It also acts as a diuretic, an antidepressant, and as a precursor of corticosteroids and of other sex hormones, notably estrogen and testosterone. There is also evidence that progesterone affords protection against loss of libido, osteoporosis, endometrial cancer, breast cancer, and fibrotic cysts.
When the child-bearing years draw to a close, every woman experiences a decline in the production of progesterone, and consequently, a decline in all of the hormones that are synthesized from progesterone. This decline significantly and negatively affects both life-span and quality of life (Ettinger, 1996, Obst. and Gyne. 87:6-12; Karlberg et al., 1995, Acta. Obstet. Gynecol. Scand. 74:367-372). In addition to the uncomfortable symptoms, such as hot flashes, that are frequently experienced at around the time of menopause, there is an increase in the prevalence of life-threatening conditions, including heart disease, osteoporosis, and brain ischemia (more commonly called a "stroke"; Hunt et al., 1990, Br. J. Obstet. Gynecol. 97:1080-1086). These conditions exact a high personal price and consume significant medical resources. Postmenopausal osteoporosis, the most common metabolic bone disorder in the United States, is the underlying cause of over 1.3 million fractures, at an estimated cost of over $10 billion annually.
Currently, the most common form of treatment for postmenopausal osteoporosis, as well as the other complex physiological conditions associated with menopause, is oral administration of estrogen, either alone or in combination with synthetic progestins. It is estimated that women under the age of 85 who adhere to a program of hormone replacement therapy (HRT) reduce their risk of having a fatal stroke or heart attack by 50-60% (Paganini-Hill et al., 1988, Br. Med. J. 297:519; Henderson et al., 1988, Am. J. Obstet. Gynecol. 159:312). Not only does overall longevity increase (Folsom et al., 1995, Am. J. Public Health 85:1128-1132), but quality of life is improved by HRT as measured by indices of mood, sleep quality, sexual satisfaction, memory, and skin tone, and by bone densimetry (Purdic et al., 1995, Br. J. Obstet. Gynaecol. 102:735-739; Sherwin, 1991, J. Clin. Endocrinol. Metab. 72:336-343; Kimura et al., 1995, Horm. Behav. 29:312-321; Jaliman, 1995, Menopause Mgmt. July/Aug. 34-38; Genant et al., 1989, Am. J. Obst. Gynecol. 161:1842).
There are substantial side effects associated with current hormone replacement therapies (Lee supra; see also Darj, 1992, Maturitas 15:209; Glueck, 1995, J. Lab. Clin. Med. 123:59; Hillard, 1992, Fert. Steril. 58:959-963). For example, administration of unopposed estrogen has been associated with an increased risk of endometrial hyperplasia and adenocarcinoma in women with an intact uterus (Samsioe, 1992, Am. J. Obstet. Gynecol. 166:1980-1985; Ziel et al., 1975, N. Engl. J. Med. 293:1167-1170) and with an increased incidence of breast cancer, regardless of whether or not the patient has had a hysterectomy. Therefore, postmenopausal women who have had breast or endometrial cancer, or who have a strong family history of these cancers, are generally considered poor candidates for many currently prescribed hormone replacements.
Similarly, synthetic progestins are contraindicated for women with known or suspected malignancies of the breast or genital organs, and are associated with a number of undesirable side effects. For example, medroxyprogesterone acetate, a commonly prescribed progestin, carries warnings that it may cause or contribute to pulmonary embolism, cerebral thrombosis, mental depression, nausea, insomnia, fluid retention, migraine headache, renal dysfunction, weight gain, and acne. It is, therefore, not surprising that 30% of the patients for whom HRT is prescribed will never even fill their prescriptions (Ravnikar, 1987, Am. J. Obstet. Gynecol. 156:1332).
In addition to undesirable and potentially lethal side effects, several other factors contribute to the underutilization of HRT world-wide. These include the fear of contracting cancer, the concept that medication is given only to treat illness, rather than to promote wellness, and the related psychological barrier constructed by those who believe that following a program of HRT represents a woman's personal failure to manage her own feminity without chemical intervention.